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Purpose <p>Metabolic reprogramming allows cancer cells to survive and proliferate under nutrient-deprived conditions. Uridine, a central molecule in pyrimidine metabolism, supports both nucleotide biosynthesis and redox homeostasis. However, high-sensitivity imaging tools for equilibrative nucleoside transporter 1 (ENT1)-mediated uridine transport are lacking, limiting applications in precise diagnosis and intraoperative guidance. This study aimed to develop and validate a novel dual-modality imaging platform targeting ENT1-mediated uridine transport for tumor imaging and surgical navigation. </p> Methods <p>We synthesized [<sup>68</sup>Ga]Ga-DOTA-FZUD and ICG-FZUD probes for PET and NIR-II fluorescence imaging, respectively. Small-animal PET/CT and NIR-II fluorescence imaging were performed, and biodistribution were analyzed. Ex vivo NIR-II fluorescence imaging using ICG-FZUD was performed on surgical specimens from three gastric cancer patients to confirm tumor targeting.</p> Results <p>&#xa0;[<sup>68</sup>Ga]Ga-DOTA-FZUD exhibited excellent radiochemical purity. In pancreatic cancer models with relatively higher ENT1 expression (AsPC-1, Panc-1) compared with lower ENT1 expression models (MiaPaCa-2, BxPC-3), [<sup>68</sup>Ga]Ga-DOTA-FZUD demonstrated markedly greater tumor uptake. Similar uptake was also observed in gastric, breast, and glioblastoma models, with tumor-to-muscle ratios consistently exceeding 3.5. ICG-FZUD enabled high-contrast NIR-II imaging and clearly delineated tumor margins. Notably, ICG-FZUD penetrated the blood–brain barrier and visualized orthotopic glioblastoma. Ex vivo imaging of human gastric cancer tissues confirmed selective tumor uptake, consistent with histopathological findings. </p> Conclusion <p>This ENT1-targeted uridine transport PET/NIRF dual-modality imaging platform complements conventional glucose-based imaging and provides real-time intraoperative navigation. It holds significant promise for early cancer diagnosis and precision surgery with strong translational potential.</p> Graphical Abstract <p></p> <p>We developed a first-in-class dual-modality imaging probe targeting uridine metabolism, integrating [<sup>68</sup>Ga]Ga-DOTA-FZUD for PET and ICG-FZUD for NIR-II fluorescence imaging. These probes enter tumor cells via ENT1 and demonstrate excellent tumor specificity, in vivo stability, and pharmacokinetics across multiple models. They enable clear delineation of tumor margins, including in orthotopic glioblastoma. Ex vivo imaging of patient specimens further supports their translational potential for non-glucose metabolic imaging and intraoperative navigation.</p>

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Uridine-Based PET/NIRF Dual-Modality imaging for precision tumor diagnosis and surgery

  • 期刊论文

  • 发表日期：

    2025年9月24日

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  • Linjie Bian,
  • Panli Li,
  • Yigang Chen,
  • Simin He,
  • Jianping Zhang,
  • Xiaoping Xu,
  • Jindian Li,
  • Shaoli Song

摘要

Purpose

Metabolic reprogramming allows cancer cells to survive and proliferate under nutrient-deprived conditions. Uridine, a central molecule in pyrimidine metabolism, supports both nucleotide biosynthesis and redox homeostasis. However, high-sensitivity imaging tools for equilibrative nucleoside transporter 1 (ENT1)-mediated uridine transport are lacking, limiting applications in precise diagnosis and intraoperative guidance. This study aimed to develop and validate a novel dual-modality imaging platform targeting ENT1-mediated uridine transport for tumor imaging and surgical navigation.

Methods

We synthesized [68Ga]Ga-DOTA-FZUD and ICG-FZUD probes for PET and NIR-II fluorescence imaging, respectively. Small-animal PET/CT and NIR-II fluorescence imaging were performed, and biodistribution were analyzed. Ex vivo NIR-II fluorescence imaging using ICG-FZUD was performed on surgical specimens from three gastric cancer patients to confirm tumor targeting.

Results

 [68Ga]Ga-DOTA-FZUD exhibited excellent radiochemical purity. In pancreatic cancer models with relatively higher ENT1 expression (AsPC-1, Panc-1) compared with lower ENT1 expression models (MiaPaCa-2, BxPC-3), [68Ga]Ga-DOTA-FZUD demonstrated markedly greater tumor uptake. Similar uptake was also observed in gastric, breast, and glioblastoma models, with tumor-to-muscle ratios consistently exceeding 3.5. ICG-FZUD enabled high-contrast NIR-II imaging and clearly delineated tumor margins. Notably, ICG-FZUD penetrated the blood–brain barrier and visualized orthotopic glioblastoma. Ex vivo imaging of human gastric cancer tissues confirmed selective tumor uptake, consistent with histopathological findings.

Conclusion

This ENT1-targeted uridine transport PET/NIRF dual-modality imaging platform complements conventional glucose-based imaging and provides real-time intraoperative navigation. It holds significant promise for early cancer diagnosis and precision surgery with strong translational potential.

Graphical Abstract

We developed a first-in-class dual-modality imaging probe targeting uridine metabolism, integrating [68Ga]Ga-DOTA-FZUD for PET and ICG-FZUD for NIR-II fluorescence imaging. These probes enter tumor cells via ENT1 and demonstrate excellent tumor specificity, in vivo stability, and pharmacokinetics across multiple models. They enable clear delineation of tumor margins, including in orthotopic glioblastoma. Ex vivo imaging of patient specimens further supports their translational potential for non-glucose metabolic imaging and intraoperative navigation.